Amyloid deposition occurs in more than twenty different human diseases. This project is concerned with amyloid formation by Islet Amyloid Polypeptide (IAPP), the endocrine hormone responsible for pancreatic islet amyloid in type 2 diabetes. Islet amyloid significantly contributes to the pathology of type 2 diabetes and is also a major problem in islet cell transplantation. Comparatively little is known about amyloid formation by IAPP despite its obvious importance and the mechanism underlying islet amyloid formation is not understood. The studies outlined here will;(1) determine the mechanism of amyloid formation by IAPP;(2) deduce the role of proIAPP processing intermediates in amyloid formation, a topic which has emerged as a critical issue in the last year (3) develop inhibitors of amyloid formation by IAPP and proIAPP and (4) test a general strategy for improving existing inhibitors of amyloid formation. The lessons learned will provide insight into strategies for the treatment and prevention of type 2 diabetes, and are expected to aid efforts to better control pathological amyloid formation in other diseases. An interdisciplinary combination of experimental biophysics, cell biology, and molecular dynamics simulations will be used to address these issues. Three specific aims will be carried out. The first involves studies of the mechanism of amyloid formation by IAPP and is made up of four synergistic sub aims: A) The effects of modulating the conformational ensemble of monomeric IAPP on the kinetics of fibril formation will be determined;B) The hypothesis that a helical intermediate plays a critical role in amyloid formation by IAPP will be tested;C) The changes in secondary structure that occur during IAPP fibril formation will be defined with residue specific resolution;D) The role individual side chains play in amyloid formation by IAPP will be defined. The second aim will define the role of pro-IAPP processing intermediates in amyloid formation. The third aim will lead to the development of new inhibitors of amyloid formation by IAPP and test their ability to inhibit cell death. A general methodology for improving existing inhibitors will be tested as part of aim-3.